The mouse W locus controls important steps in the development of three distinct cell lineages: gametogenesis, hematopoiesis and pigment cell formation. Recent genetic and molecular data has suggested a close relationship and likely identity between the mouse W gene locus and the cellular proto-oncogene c-kit. The objective of this program, therefore, is to investigate the role that the c-kit gene, which encodes a transmembrane tyrosine kinase growth factor receptor, plays in these important developmental processes. The experimental approaches will involve molecular characterization of the c-kit gene and its RNA and protein products in W mutant mice; in situ RNA analysis of c-kit expression in developing embryos and adult tissue from normal and W mutant mice; the generation of transgenic animals carrying the c-kit gene in their germ-line; the introduction of the c-kit gene into defective W/Wv hematopoietic stem cells using retrovirus vectors; and the generation of mice with mutations in their endogenous c- kit gene by gene targeting in mouse embryo-derived stem (ES) cells. In addition, the linkage of the c-kit gene with 'piebald trait', an inherited human skin pigmentation disorder with an associated profound mental retardation, will be investigated. These experiments should provide insights into one of the classical developmental mutations in the mouse as well as address the role that cellular proto-oncogenes play in the development of normal mice and humans.